Characterization of MafB/c-Maf deficient macrophages as cancer immunotherapy

• Applicant: Dr. Julien Subburayalu
• Subject Area: Hematology, Oncology ; Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 498034965

Macrophages comprise a population of postmitotic, plastic immune cells capable of infiltrating tumours and to propagate cytotoxicity (1). As a key component of the natural tumour micro environment (TME), tumour-associated macrophages (TAMs) are pivotal in the context of current endeavours to deliver OncoLytic ImmunoTherapies (OLITs) (1,2). However, OLITs based on macrophages have yet to be employed successful owing to both their postmitotic phenotype and to their proclivity for repolarisation within the TME into the pro-tumorigenic M2-subtype (1,2), which severely impairs the extent of the adaptive immune response ultimately culminating in T cell exhaustion. Consequentially, several approaches to deliver OLITs either aim to prevent or reverse the process of macrophage repolarisation within the TME. For example, kitting out macrophages with a chimeric antigen receptor (CAR) to eat away at solid tumour cells has recently been employed successfully. Here, CAR-macrophages specifically phagocytosed tumour cells, were associated with the pro-inflammatory phenotype (M1) and could, intriguingly, convert TAMs to the M1-subtype (3). Preliminary work in a syngeneic murine model of the Sieweke group has determined that the genetic ablation of MafB/c-Maf transcription factors in the absence of specific CARs favoured the M1-subtype whilst conferring direct and indirect oncolytic effects, too.The development of human MafB/c-Maf double knock-out macrophages (MafB/c-Maf DKOs) could render OLITs based on macrophages feasible in due course. MafB/c-Maf DKOs are characterised by a continuous expansion of terminally differentiated macrophages in vitro without posing a hazard regarding tumorigenesis in vivo (4). Moreover, Maf transcription factors appear to denote a crucial immune checkpoint to determine the fate between reactivity or tolerance. Cytokines, which drive the M1 polarisation programme in macrophages, e.g., IFN-g or TNF-a, down-regulate the expression of Maf on the level of promotors and enhancers alike (5,6). Conversely, c-Maf deficiency and inhibition were recently shown to curtail the extent of M2 polarisation in a murine model of lung cancer and in humans (7).Therefore, in this project I endeavour to determine the potential of human MafB/c-Maf DKOs as OLIT based on macrophages. For this reason, I will initially validate that also the genetic ablation of both MafB and c-Maf is denoted by a fixed pro-inflammatory phenotype (M1) on the level of promotors, enhancers, and the provided transcriptome in response to typical human tumour transcription profiles identified recently (8). Ultimately, MafB/c-Maf DKOs will be comprehensively validated in a preclinical xenotransplant model in vivo using human models of ovarian (SK-OV-3) or lung cancer (A549), respectively, in humanised mice.PMIDs:1)281174162)290651073)323617134)198929885)288136576)288257017)319450188)29628290

• DFG Programme: WBP Position